An individual's neighborhood provides important context for cardiovascular disease risk, and neighborhood characteristics as defined by U.S. census-level socioeconomic measures or the social and physical environment in which an individual lives have been associated with cardiovascular disease and prevalent cardiovascular risk factors. Obesity as a cardiovascular risk factor appears to be particularly influenced by an individual's neighborhood environment. The exponential rise in obesity prevalence over only three decades, with more than one-third of the U.S. population now having a body mass index (BMI) 30 kg/m2, is largely consistent with behavioral and environmental rather than biological causal factors. Prior cross-sectional studies support a relationship between neighborhood socioeconomic status (SES), prevalent obesity and prevalent cardio-metabolic risk factors. However, these results are likely subject to self-selection bias, or a tendency for healthier, more financially secure individuals to live in areas of higher SES. Few longitudinal studies have evaluated the relationship between neighborhood SES and weight gain. Results have been mixed, with some showing no significant associations between neighborhood SES and weight trajectory, and others demonstrating that lower neighborhood SES can predict weight gain and incident obesity. Lack of access to resources for physical activity and a healthful diet, the influence of neighborhood characteristics on psychosocial stress, and the impact of social norms across neighborhood environments of varying socioeconomic levels are potential mechanisms by which neighborhood-level SES may influence weight change over time. However, the relative contribution of psychosocial factors and access to physical activity, particularly in the relationship between neighborhood SES and weight change over time, has not been fully elucidated. Therefore, we examined the relationship between neighborhood-level socioeconomic deprivation and weight change among non-movers (N=939) in the Dallas Heart Study (DHS), a multi-ethnic, population-based sample of Dallas County residents aged 18-65. DHS participants underwent weight measurements in 2000-02 and 2007-09 with median 7-year follow-up and geocoded home addresses defined their neighborhood block groups in Dallas County. A block-group level neighborhood deprivation index (NDI) for DHS participants was created, with higher scores indicating more socioeconomic deprivation. Repeated-measures linear mixed modeling with random effects was used to determine weight change (kg) relative to NDI as a continuous variable. Reported physical activity and perceptions of neighborhood environment (questionnaire-derived score with higher score = more unfavorable perceptions of neighborhood) were examined as mediators. Length of residence in neighborhood was examined as an effect modifier in the relationship. There was a statistically significant interaction between length of neighborhood residence and neighborhood deprivation index as continuous variables (p-interaction=0.04) and results were stratified by median length of residence in neighborhood ( median length of residence of 11 years and > median length of residence of 11 years). DHS participants living in more socioeconomically deprived neighborhoods had lower income and education (p-trend <0.001 for both). Blacks were more likely to live in more socioeconomically deprived neighborhoods than whites and Hispanics (p<0.001). Adjusting for age, sex, race, smoking, education, and income, DHS participants who lived in their neighborhood the longest period of time (over median of 11 years) gained 1.0 more kilograms in weight over the 7-year period (p=0.03) for every one-unit increment of NDI. This equated to up to 5.8 kg of weight gain for participants in the highest NDI tertile. Greater neighborhood-level socioeconomic deprivation remained associated with weight gain after adjustment for physical activity levels (p=0.02) and perceptions of neighborhood environment (p=0.04) for those living in their neighborhood the longest period of time. In contrast, for those who lived in their neighborhood median 11 years, there was no significant relationship between neighborhood deprivation and weight change in unadjusted and adjusted models. Thus, living in more socioeconomically deprived neighborhoods over a longer period of time is associated with weight gain among DHS participants. This relationship does not appear to be explained by lower levels of physical activity or unfavorable perceptions of the neighborhood environment. In Dallas County, the high risk for weight gain for people with long-term exposure to socioeconomically deprived neighborhoods supports the need to develop targeted community-based interventions to address obesity and reduce disparities in cardiovascular risk.